Atezolizumab and Cobimetinib in Treating Patients With Metastatic, Recurrent, or Refractory Non-small Cell Lung Cancer

  • End date
    Jul 17, 2024
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 23 August 2023
ct scan
monoclonal antibodies
measurable disease
antiretroviral therapy
lung cancer
gilbert's syndrome
serum bilirubin level
neutrophil count
tumor cells
monoclonal antibody therapy


This phase II trial studies how well atezolizumab and cobimetinib work in treating patients with non-small cell lung cancer that has spread from where it first started (primary site) to other places in the body (metastatic), has come back (recurrent), or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cobimetinib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving atezolizumab and cobimetinib may work better in treating patients with non-small cell lung cancer.



I. To evaluate durable overall response rate with atezolizumab plus cobimetinib in patients with metastatic non-small cell lung cancer (NSCLC) resistant or refractory to prior PD-1 or PD-L1 therapy.


I. To evaluate the overall response rate of atezolizumab plus cobimetinib in patients with metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.

II. To evaluate the progression-free survival (PFS) of atezolizumab plus cobimetinib in patients with metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.

III. To evaluate the overall survival (OS) of atezolizumab plus cobimetinib in patients with metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.

IV. To evaluate the duration of response (DOR) of atezolizumab plus cobimetinib in patients with metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.

V. To evaluate the grade 3 and 4 toxicity rate in patients with metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy when treated with atezolizumab plus cobimetinib.


I. To evaluate the consequences of treatment with atezolizumab plus cobimetinib on the tumor microenvironment in patients with metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.

II. To correlate genomic characteristics including tumor mutation burden to response to therapy with atezolizumab plus cobimetinib in patients with metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.


Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1 and cobimetinib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Patients also undergo a computed tomography (CT) scan, magnetic resonance imaging (MRI), biopsy, and collection of blood throughout the trial.

After completion of study treatment, patients are followed up for 90 days.

Condition Metastatic Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Refractory Lung Non-Small Cell Carcinoma, Stage IV Lung Non-Small Cell Cancer AJCC v7
Treatment laboratory biomarker analysis, biopsy, computed tomography, magnetic resonance imaging, biospecimen collection, Cobimetinib, Atezolizumab
Clinical Study IdentifierNCT03600701
SponsorNational Cancer Institute (NCI)
Last Modified on23 August 2023


Yes No Not Sure

Inclusion Criteria

Patients must have histologically or cytologically confirmed metastatic or recurrent non-small cell lung cancer (any histology is permitted)
Presence of a mutation in KRAS as detected by a Clinical Laboratory Improvement Act (CLIA)-approved assay is required for patients enrolled in cohort 1; central validation is not required for enrollment
Absence of a mutation in KRAS (KRAS wild type) is required for patients enrolled in cohort 2; central validation is not required for enrollment but KRAS mutation status must be known, regardless of histology
Patients must have primary resistance to anti-PD-1 or anti-PD-L1 therapy, given as
Patients must have disease amenable to core biopsy and be willing to undergo the required research biopsies
Anti-PD-1 or anti-PD-L1 therapy does not need to be the most recent therapy prior to study enrollment
monotherapy or in combination with other agents; patients must have
experienced progressive disease within 6 months (180 days) of initiating
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
treatment with a PD-1/PD-L1 inhibitor
Leukocytes >= 2,500/mcL
Age >= 18 years
Absolute neutrophil count >= 1,000/mcL
Because no dosing or adverse event data are currently available on the use of atezolizumab in combination with cobimetinib in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
Patients with a sensitizing alteration in EGFR, ALK or ROS1 are eligible provided they
Platelets >= 100,000/mcL
have experienced disease progression or intolerance to treatment with an
Hemoglobin >= 8 g/dL
approved EGFR, ALK or ROS1 inhibitor, respectively; patients who have received
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x upper limit of normal [ULN] may be enrolled)
investigational inhibitors may be eligible following discussion with the study
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)
principal investigator (PI)
Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver involvement or bone metastases)
Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam
Institutional normalized ratio (INR) and partial thromboplastin time (aPTT) =< 1.5 x ULN; (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose)
Administration of atezolizumab or cobimetinib may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of study agent; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
Ability to understand and the willingness to sign a written informed consent document
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

Exclusion Criteria

Patients who have not recovered from clinically significant adverse events (other than alopecia) due to prior anti-cancer therapy
Treatment with any investigational agent within 4 weeks prior to cycle 1, day 1
Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1
Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
Patients with symptomatic central nervous system (CNS) metastases are excluded
Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met
Evaluable or measurable disease outside the CNS
No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
No history of intracranial hemorrhage or spinal cord hemorrhage
No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted
No neurosurgical resection or brain biopsy within 28 days prior to cycle 1, day 1
No stereotactic radiation or whole-brain radiation within 28 days prior to cycle 1, day 1
Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
History of allergic reactions attributed to compounds of similar chemical or biologic composition to atezolizumab or cobimetinib
Cardiac ejection fraction below institutional lower limit of normal (LLN) or below 50%, whichever is lower, as determined by echocardiogram or multigated acquisition (MUGA) scan within 4 weeks of cycle 1, day 1
History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
Any grade 3 or above hemorrhage or bleeding event within 4 weeks prior to initiation of study treatment
History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to initiation of study treatment
History of congenital long QT syndrome or corrected QT interval (QTc) by Fridericia Formula > 450 msec within 28 days of cycle 1, day 1
Patients with asymptomatic treated CNS metastases may be enrolled, provided all
Patients receiving any medications or substances that are strong or moderate inhibitors or inducers of CYP3A4 enzymes are ineligible; these include St. John's wort or hyperforin (potent CYP3A4 enzyme inducer) and grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor); because the lists of these agents are constantly changing, it is important to regularly consult medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
the criteria listed above are met as well as the following
Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study
Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
Has a known concurrent malignancy that is expected to require active treatment within
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
two years, or may interfere with the interpretation of the efficacy and safety
Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible
outcomes of this study in the opinion of the treating investigator
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions
superficial bladder cancer, non-melanoma skin cancers, or low grade prostate
Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
cancer not requiring therapy should not exclude participation in this trial
Rash must cover less than 10% of body surface area (BSA)
Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
Any significant active infection requiring treatment within 14 days prior to cycle 1, day 1
Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of need for a major surgical procedure during the course of the study
Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab
Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuated influenza vaccine within 4 weeks prior to cycle 1, day 1 or at any time during the study
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active tuberculosis (TB), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant women are excluded from this study because both atezolizumab and cobimetinib are expected to cause fetal harm if used during pregnancy; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cobimetinib or atezolizumab, breastfeeding should be discontinued if the mother is treated with either therapy; these potential risks may also apply to other agents used in this study
Inability or unwillingness to swallow pills
History or risk of autoimmune disease, including, but not limited to, systemic lupus
History of malabsorption syndrome or other condition that would interfere with enteral absorption
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular
thrombosis associated with antiphospholipid syndrome, autoimmune hemolytic
anemia, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-
Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced)
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest
computed tomography (CT) scan; history of radiation pneumonitis in the
radiation field (fibrosis) is permitted
Uncontrolled pleural or pericardial effusion or ascites requiring recurrent drainage
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